Perigaud, C., et al, Nucleosides and Nucleotides, 11(2-4), 903-945 (1992), provide a useful overview of the current state of the art relating to the use of nucleosides and/or nucleotides as chemotherapeutic agents (including use as anticancer, antiviral and antibacterial agents). As described in this review article, the term "nucleoside(s)" relates to naturally-occurring nucleosides which are distinguished depending on the base, for example, adenine and guanine (A and G, respectively) have a purine base, whereas cytosine, uracil, thymine and hypoxanthine (C, U, T and H, respectively) have a pyrimidine base.
Nagasawa, N., et al., J. Org. Chem., 32, 251-252 (1967), describe the production of certain D-ribopyranosyl nucleosides (particularly 9-(2'-Deoxy-.beta.-D-ribopyranosyl) adenosine).
Fucik, V., et al., Nucleic Acids Research, Vol. 1, No. 4 (1974) 639-644, describe structural effects of chemical modification upon the affinity of purine nucleosides to cytidine-transport system in Bacillus subtilis using a series of modified derivatives including certain ribopyranosyl nucleosides.
Baud, M. V., et al., Tetrahedron Letters, Vol. 31, No. 31, pp. 4437-4440 (1990), describes the synthesis of certain 2'-deoxyribonucleoside compounds starting from available sugars (2-deoxyribofuranosyl or pyranosyl). The compounds described in this paper are all D-isomers.
Spadari, S., et al, J. Med. Chem, 35, pp. 4214-4220 (1992), describes certain L-.beta.-nucleosides useful for treating viral infections including Herpes Simples Virus Type I.
Holy, A., Nucleic Acid Chemistry, Vol. 1, 347-353 (1978), describes the synthesis of 2'-deoxy-L-uridine.
WO 92/08727 describes certain 2'-L-desoxyuridines and their use for treating viruses.
As is well known, sugars found in natural nucleic acids are D-ribose and D-deoxyribose in almost all cases. Much research has been done to investigate the chemical, and biological activities of the D-isomers of ribonucleotides and ribonucleosides, however, far less work has been done with the L-isomers. This is primarily due to the fact that the synthesis of the L-isomers is much more difficult, often involving the optical resolution of the D,L-isomers of nucleosides with the aid of microorganisms and enzymes. (See generally, Asai, M., et al., Chem. Pharm. Bull., 15(12), 1863-1870 (1967).) The known activity of D-nucleoside compounds, and the successful commercialization of several of such D-sugar-nucleoside compounds, (see Perigaud, C., et al., supra, for a discussion of D-nucleoside analogs which have gained commercial acceptance) led in-part to the present work relating to the L-isomers of certain nucleoside analogs.
Perhaps the best known commercial nucleobase analog is 5-fluorouracil (5-FU) the structure of which is shown below: ##STR1##
5-FU is commercially available from Roche and is one of the most commonly used drugs for treating certain types of cancer. The high acceptance of this drug is due in part to its extreme cytotoxic effects. However, it also has a narrow margin of safety and is, therefore, associated with many serious side effects including, for example, nausea, vomiting, diarrhea, alopecia, leukopenia, thrombocytopenia, etc. Additionally, 5-FU is primarily used in an intravenous formulation.
5-FU is currently dosed at short intervals due to the damage it does to normal cells. The patient is taken off chemotherapy for a time to allow recovery from the cytotoxic effects of the treatment. It is contemplated that if a drug is developed that is less cytotoxic to healthy cells it would no longer be necessary to treat the patient in periodic intervals, which may be associated with the development of multiple drug resistance often exhibited in treated cancer cells. Specifically, as a tumor is being killed the cells that are most resistant to the drug die slower and, therefore, when the treatment is stopped (often because of the toxicity to normal cells) the more resistant tumor cells are left to multiply.
A significant commercial nucleoside analog is azidothymidine (AZT), commercially available as Retrovir from Burroughs Wellcome. AZT, a .beta.-D-deoxy-ribofuranosyl derivative of the formula: ##STR2## is useful as an antiviral agent, particularly against the virus responsible for the Acquired Immune Deficiency Syndrome (AIDS).
This compound, like 5-FU, is associated with a number of undesirable side effects including hematologic toxicity such as granulocytopenia and/or severe anemia.
Without intending to be limited, applicants believe that the L-nucleoside compounds as claimed in the present invention may be beneficial over compounds such as 5-FU and AZT since it is believed that L-nucleosides (as claimed) exhibit selective permeability to compromised cells. By compromised cells we mean cells such as cancer cells or other infected cells, whether the infection is bacterial, fungal, viral or parasitic. It is believed that the L-nucleosides of the present invention may be transported into or permeate these compromised cells, whereas in normal cells the L-nucleosides would not permeate. (See for example, Lin, T. S., et al., Abstract entitled "Synthesis and Biological Evaluation of 2',3'-Dideoxy-L-Pyrimidine Nucleosides as Potential Antiviral Agents against HIV and HBV", published J. Med. Chem., 37 (1994) 798-803; and Spadari, S., et al., J. Med. Chem., 35 (1992) 4214-4220.) Therefore, to the extent these L-nucleosides are selective for compromised cells, they are less harmful to normal cells than compounds like 5-FU.
In addition to this concept of selective permeability, in viral-infected cells where therapeutic compounds often have an inhibitory mechanism related to the RNA of the cell, it is contemplated that the enzymes of such viral-infected cells may be less specific than in a normal cell and, therefore, if you can permeate the cell with an L-nucleoside, a more primitive enzyme such as an organic phosphorylases, kinases or thymidilate synthase may recognize the compound in such a way as to cause inhibition.
Therefore, although certain nucleoside analogs and/or nucleobase analogs have been commercialized for indications such as cancer and/or AIDs treatment, there is a need for a nucleoside analog which is perhaps as cytotoxic as 5-FU or is less cytotoxic but more specific than 5-FU for cancer therapy and/or a compound which is more effective and/or better tolerated than AZT for treatment of viruses.
The present invention relates to a novel group of such L-ribofuranosyl nucleosides which have interesting activity as anticancer, antiviral, antiparasitic, antifungal, antibacterial and/or antimicrobial agents. These compounds are generally water soluble, which suggests that oral deliver may be achieved, and the activity of these compounds may be more selective for compromised cells as compared to normal cells.